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Real-time Endpoint Monitoring and Determination for a Pharmaceutical Salt Formation Process With In-Line FT-IR Spectroscopy

Real-time Endpoint Monitoring and Determination for a Pharmaceutical Salt Formation Process With In-Line FT-IR Spectroscopy

Zhihao Lin, Lili Zhou, Amar Mahajan, Sherry Song, Tao Wang, Zhihong Ge, Dean Ellison

J Pharm Biomed Anal. 2006 Apr 11;41(1):99-104.

PMID: 16321495

Abstract:

An application of Fourier transform infrared (FT-IR) spectroscopy equipped with an attenuated total reflectance (ATR) probe for in-line monitoring of a hydrochloride (HCl) salt formation process of 4-{1-methyl-2-piperidin-4-yl-4-[3-(trifluorometryl)phenyl]-1H-imidazol-5-yl}-N-[(1S)-1-phenylethyl]pyridine-2-amine (freebase), an active pharmaceutical ingredient as a P38 MAP kinase inhibitor, is described. The freebase forms both mono- and bis-HCl salts due to its structural features. The mono-HCl salt is the desired product but the bis-salt is an impurity. The key to maximizing the product yield and minimizing the impurity level is to monitor the salt-forming reaction and to terminate it at the correct HCl charge amount. The process analytical technology (PAT) provided real-time data for process control and overcame the limitations that had been previously encountered by other analytical instrumentations, such as high-performance liquid chromatography and titration. Two qualitative approaches for reaction endpoint determination were employed. In the first approach, changes in the concentration of the freebase and bis-salt were monitored via the first derivative concentration profiles. The flat point in the freebase profile and the rise in the bis-salt profile were used as a detection bracket for the endpoint of HCl charging. In the second approach, principal component analysis (PCA) was used to classify the status of the process based on a spectral library consisting of spectra collected around the endpoint. Results indicated that both methods provided adequate accuracy for endpoint control in a small window between 1.0 and 1.05 HCl to freebase mole ratio. Both methods were used to support a scaled up process. Three batches of MAP mono-HCl salt formation were successfully controlled and prepared.

Chemicals Related in the Paper:

Catalog Number	Product Name	Structure	CAS Number	Price
ALP261769442	BMS-281384 bis-HCl		261769-44-2 (free base)	Price

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